Abstract Sickle cell disease (SCD) is a genetic disorder and the most common hemoglobin disorder in the United States (U.S.). It affects an estimated 90,000-100,000 Americans and was ranked as the fifth most common principal diagnosis for Medicaid?s super-utilizer hospital stays. Painful vaso-occlusive episodes (VOE), a new onset of pain (7/10 or greater) for at least four hours for which there is no other explanation than vaso-occlusion, are the most common manifestation of SCD experienced by patients and the most common reason for emergency department (ED) visits. There is no standard, evidence based approach to treating painful VOE. In 2014 the National Heart, Lung, and Blood Institute (NHLBI) released recommendations for the ?Management of Sickle Cell Disease? where recommendations to treat VOE were based on consensus panel expertise due to lack of evidence. Recommendations included the use of a patient specific protocol (specific agents and doses for an individual patient) or a standard VOE analgesic protocol, where the standard VOE protocol was not defined. We implemented a weight-based analgesic protocol as a ?standard? VOE protocol and conducted a pilot randomized clinical trial (RCT) at two EDs with 52 patients comparing the patient-specific and weight-based analgesic protocols; results were encouraging, however, limited due to small numbers of patients and sites. We propose a Phase III randomized and single-blinded (with subject blinded) clinical trial to test the hypothesis that the patient-specific analgesic protocol is clinically superior to the weight-based analgesic protocol for treating SCD patients with an ED visit due to VOE. This five-site RCT will randomize 460 adult SCD patients to one of the two protocols in order to have the target of 230 patients with an ED visit for VOE during the 24 month enrollment period. A sample size of 230 patients will provide 90% power for detecting a 14 mm clinically significant difference between the two protocols in the primary endpoint, pain score reduction from arrival in the ED to discharge by using a 0-100 mm visual analog scale. Secondary outcomes include ED length of stay, hospitalization, seven day return ED visits and hospitalizations and we will monitor side effects and safety. A Clinical Coordinating Center (CCC; Paula Tanabe, PI) and a Data Coordinating Center (DCC; Huiman Barnhart, PI) will manage this trial. This experienced multi-specialty team will deliver the integrated services vital to the trial, including clinical and operational leaderships, site management, statistical analysis and data management. High level evidence generated by this trial will shift the paradigm on treating VOE in the ED and decreasing the pain of SCD patients suffering from this devastating complication.